Azoxybis(2-phenylacrylic acid,3-tropanyl esters)



United States Patent 3,503,952 AZOXYBIS[Z-PHENYLACRYLIC ACID,

' 3-TROPANYL ESTERS] Henry C. Caldwell, Ambler, and William G. Groves, Norristown, Pa., assignors to Smith Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Filed June 5, 1967, Ser. No. 643,371

Int. Cl. C07c 105/00; A61k 27/00 U.S. Cl. 260-143 9 Claims ABSTRACT OF THE DISCLOSURE Substituted azoxydiphenylbis[2-phenylacrylic acid, 3- tropanyl esters] having gastrointestinal spasmolytic activity. The substituent on the 3 carbon atom of the 2-phenylacrylic acid derivatives being hydrogen, phenyl, furyl, thienyl and pyridyl and the diphenyl substituents optionally being halogen, lower alkyl, lower alkoxy and hy droxy. Method of preparation comprises reacting the properly substituted nitrophenylacetic acid with paraformaldehyde or an aromatic aldehyde, treating the formed acid with tropine or thiotropine and converting the resulting ester to the final azoxy derivative by reducing with platinum on carbon.

This invention relates to novel substituted azoxybis[2- phenylacrylic acid, 3-tropanyl esters] which have useful pharmacodynamic activity. More specifically, the compounds of this invention possess gastrointestinal spasmolytic activity as demonstrated in standard animal pharmacological test procedures. For example, in the modified Janssen test for the inhibition of fecal pellet count, spasmolytic activity was observed at doses of 12.5 mg./ kg. and 62.5 mg./kg. in mice.

These novel compounds are particularly advantageous because they produce the spasmolytic activity Without the concomitant mydriatic and antisalivary side effects which are common to known anticholinergic-antispasmodic drugs. Prior to the present invention, there has been a great need for compounds which produce spasmolytic activity without the usual antichlorinergic side effects, such as, for example, dry mouth, blurred vision and uninary retention which are common to known anticholinergic-antispasmodic drugs. The need of safe and effective compounds free of the above-noted side effects and having spasmolytic activity has been great.

3,503,952 Patented Mar. 31, 1970 ice The novel substituted azoxy tropanyl esters of this invention are represented by the following general formula:

FORMULA 1 N-CHa I when:

Advantageous compounds of this invention are represented by the above structural formula when R represents phenyl and R represents halogen such as chloro, bromo, or fiuoro, methoxy or ethoxy.

The preferred and most advantageous compound of this invention is represented by the following structural formula:

FORMULA 2 t 0 eN QWLKW:

The substituted azoxybis[2-pheny1acrylic acid-3-tropan yl esters] are prepared according to the following synthetic procedure:

R1 /E R2 (CH C0)02 H C-COOH So C1 tropine or thiotropine salt N-CHa l l 0 R2 I I Q-d-m- N-0H, A

N-CHa N0:

The .method is carried out using readily available starting materials and gives excellent yields of the end product. Where certain compounds desired for use as starting materials are not available they can be prepared by methods described in the literature and well known to the art for preparing analogous compounds as described in the examples. For example, the thiotropine is prepared by reducing tropinone with hydrogen sulfide or sulfur as detailed in Ind. Eng. Chem., 42, 2547 (50), for the reduction of cyclohexanone to cyclohexanethiol.

The properly substituted nitrophenylacetic acid is converted to the tropic acid derivative by placing the acid in an organic solvent, preferably benzene and slowly adding it to a refluxmixture of ether, magnesium turnings and isopropyl chloride. The mixture is then refluxed for approximately two hours after the addition of the acid .is completed and then cooled. Paraformaldehyde is then distilled into the mixture with .stirring. The mixture is then poured into ice and concentrated sulfuric acid and again stirred. The crude solid which forms is then filtered and recrystallized from water and dried. The solid is further purified by treatment with hot water and benzene. The product is filtered from cool aqueous solution to yield the properly substituted nitrotropic acid.

The tropic acid derivative is then converted to the desired 3-tropanyl 2-phenyl acrylate by preparing a solution of the tropic acid in acetyl chloride and refluxing. Thionyl chloride is then added with continued refluxing. The excess thionyl chloride is removed and either tropine or thiotropine hydrobromide in pyridine is added and the mixture heated. The mixture is cooled with the addition of water and the resultant-solid filtered and recrystallized from water to yield the desired 3-tropanyl-2-phenyl acrylate derivative.

The corresponding 3-substituted 2phenylacrylic acid derivatives are prepared by reacting the properly substituted nitrophenylacetic acid with an aromatic aldehyde in an organic solvent such as acetic anhydride and using a tertiary amine such is thiethylamine, pyridine or N,N'- dimethylaniline as a catalyst. The mixture is then heated.

The resulting 3-substituted 2-phenylacrylic acid derivative is then converted to the 3-tropanyl-2-phenyl acrylate by preparing the acyl chloride or anhydride first then reacting with tropine, thiotropine or a salt thereof.

The 3-tropanyl-2-phenyl acrylate derivative is converted to the desired aZoxybis[2-phenylacrylic acid, 3-tropanyl ester] by hydrogenating over platinum on carbon.

This invention also includes nontoxic pharmaceutically acceptable addition salts of the above-defined bases formed with organic and inorganic acids. Such salts are easily prepared by methods known to the art. The base is reacted'with either the stoichiometric amount of organic or inorganic acid in aqueous miscible solvent, such as acetone or ethanol, with isolation of the salt by concentration and cooling or an excess of the acid in aqueous immiscible solvent, such as ethyl ether or chloroform, with the desired salt separating directly. Exemplary of such' organic salts are those with maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicyclic, methanesulfonic,ethanedisulfonic, acetic, propionic, tartaric, salicyclic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids as well as with the 8-halotheophyllines, for example, S-chlorotheophylline and 8- bromotheophylline. Exemplary of such inorganic salts are'those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. These salts may also be prepared by the classical method of double decomposition of appropriate salts which is Well' known to the art.

Further, exemplary of salts are nontoxic quaternary ammonium salts of the above-defined bases formed with pharmacologically acceptable lower alkyl or aralkyl esters of, for example, sulfuric, hydrohalic and aromatic sulfonic acids. These salts are prepared by treating a solution of the base in a suitable solvent, such as chloroform, acetone, benzene, toluene or ether with an excess of an organic ester of sulfuric, hydrohalic or aromatic sulfonic acid. This reaction is carried out most advantageously at a temperature in the range of from about 25 C. to about 115 C. Exemplary of such reactive esters are lower alkyl halides of a maximum of 8 carbon atoms such as methyl chloride, methyl bromide, methyl iodide, ethyl chloride, propyl bromide, butyl chloride,'isobutyl chloride, ethylene bromohydrin, ethylene chlorohydrin, allyl bromide, methallyl bromide, crotyl bromide, benzyl chloride, benzyl bromide, naphthylmethyl chloride, penethyl bromide, dimethyl sulfate, diethyl sulfate, methyl benzene sulfate and ethyl toluene sulfonate.

The novel compounds of this invention may be administered orally or parenterally in conventional dosage unit forms such as tablets, capsules, injectables or the like, by incorporating the appropriate dose of a compound of Formula 1 with carriers according to accepted pharmaceutical practices. The substituted azoxy 3-tropanyl esters of Formula 1 will be present in an amount to produce gastrointestinal spasmolytic activity. Preferably the dosage unit forms will contain the compounds of Formula 1 in an amount of from about 2.0 mg. to about 100 mg, advantageously from about 5 mg. to about 50 mg. Advantageously equal daily doses are administered one to four times daily to provide a daily dosage regimen.

The following examples are not limiting but are illustrative of this invention and the procedures for their preparation. Other variations of this invention will be obvious to those skilled in this art.

EXAMPLE 1 To a mixture containing 31.8 g. of m-nitrophenyl acetic acid, 15 ml. of benzaldehyde and 16.2 ml. of triethylamine is added with cooling 44 ml. of acetic anhydride. The mixture is stirred for approximately /2 hour and heated in an oil bath at 70 C. The temperature is raised to 100 C. over a /2 hour period and heating continued for approximately five hours. The solution is cooled and made acidic with concentrated hydrochloric acid. The crude acid is filtered, dried and recrystallized from alcohol to yield 2-m-nitrophenyl-3-phenylacrylic acid.

A suspension of 13.0 g. of 2-m-nitrophenyl-3phenylacrylic acid, 20 ml. of dry benzene and 10 ml. of thionyl chloride is warmed gently until a solution results. The clear solution is refluxed for about an hour and the excess thionyl chloride and benzene is removed by asperator. The solution is further washed with three separate portions of dry benzene. To the resulting oil is added 9.1 g. of tropine hydrobromide and the mixture is then chilled. To this mixture is added 20 ml. of dry pyridine and the solution is stirred for about /2 hour at room temperature and then at C. to 70 C. for one hour. The mixture solidifies during this process and 10 ml. of dry pyridine to dissolve the formed solid and the solution is filtered.

Hydrogen chloride is bubbled into the filtrate to yield 2,2'-m-azoxydiphenylbis[3-phenylacrylic acid, 3-tropanyl ester]dihydrochloride as a light yellow solid having a melting point of 283.5284.5 C.

EXAMPLE 2 Similarly following the procedure of Example 1, 28.3 g. of 4-bromo-3-nitrophenylacetic acid, 16.0 g. of S-nitro- 2-hydroxyphenylacetic acid, 18.0 g. of 2-nitro-4-methoxyphenylacetic acid and 20.3 g. of 3-nitro-4-methylphenylacetic acid were employed to yield respectively 2,2-mazoxydi(p-bromophenyl)bis[3 phenylacrylic acid, 3-tropanyl ester], 2,2 m-azoxydi(o hydroxyphenyl)bis[3- phenylacrylic acid, 3-tropanyl ester], 2,2'-o-azoxydi(pmethoxyphenyl)bis[3-phenylacrylic acid, 3-tropanyl ester] and 2,2-m-azoxydi(p-methylphenyl)bis[3 phenylacrylic acid, 3-tropanyl ester].

EXAMPLE 3 To a mixture under nitrogen containing 500 ml. of anhydrous ether, 27.6 g. of magnesium turnings and 11 drops of ethyl bromide is added 15 ml. of isopropyl chloride. The mixture is warmed until the reaction proceeds and 87 ml. more of isopropyl chloride is added and the mixture refluxed moderately for approximately one hour. A solution of 85.2 g. of p-nitrophenylacetic acid in 500 ml. of dry benzene is then added and the mixture further refluxed for approximately two hours. 500 g. of paraformaldehyde is then distilled into the mixture with the aid of a stream of dry nitrogen. The thick solution is stirred for about an hour after the formaldehyde distillation is completed and the mixture then poured into ice and 200 ml. of concentrated sulfuric acid, stirred and cooled to about 5 C. The crude solid is then filtered, recrystallized from water and dried at 40 C. in vacuo. The solid is then purified by treating with benzene, dissolving in hot water and extracting once again with benzene until aqueous layer is colorless. The aqueous solution is cooled and precipitate filtered to yield p-nitrotropic acid. v

20.1 g. of p-nitrotropic acid and 50 ml. of acetyl chloride are warmed gently until a solution results. The clear solution is refluxed for about an hour and the excess acetyl chloride distilled off under reduced pressure. 100 ml. of thionyl chloride is added to the residual oil and the mixture refluxed for about an hour. The excess thionyl chloride is distilled 01f, 3 separate portions of benzene added and. also distilled off. 20.0 g. of tropine hydrobromide in 35 ml. of dry pyridine is then added and heated for one hour. The mixture is cooled to about 0., water is added and the solid filtered and then recrystallized from water. The impure salt is dissolved in water and made basic with 1 N sodium hydroxide and extracted with ether. The ether solution is Washed with water and dried over anhydrous magnesium sulfate to yield 3-tropanyl-p-nitroatropate.

A solution of 23.6 g. of 3-tropanyl-p-nitroatropate in 300 ml. of methane is hydrogenated over platinum on carbon. The reaction mixture is warmed to dissolve the formed solid and the solution is filtered to yield 2,2-pazoxydiphenylbis[acrylic acid, 3-tropany1 ester].

An ethereal solution of the free base is treated with ethereal hydrogen chloride to yield the hydrochloride salt.

EXAMPLE 4 Similarly following the procedure of Example 3, 42.1 g. of 4-bromo-3-nitrophenylacetic acid, 63.0 g. of S-nitro- 2-hydroxyphenylacetic acid, 28.3 g. of 2-nitrc-4-methoxyphenylacetic acid and 31.4 g. of 3-nitro-4-methylphenylacetic acid were employed to yield respectively 2,2- m azoxydi(p bromophenyl)bis[acrylic acid, 3-tropanyl ester], 2,2-m-azoxydi(o-hydroxyphenyl)bis[acrylic acid, 3-tropanyl ester], 2,2-o-azoxydi(p-methoxyphenyl)bis- [acrylic acid, 3-tropanyl ester], and 2,2'-m-azoxydi(pmethylphenyl)bis[acrylic acid, 3-tropanyl ester].

EXAMPLE 5 To a mixture containing 60.0 g. of p-nitrophenylacetic acid, 32.1 ml. of thiophenealdehyde and 48.2 ml. of triethylamine is added 120 ml. of acetic anhydride. The mixture is heated at 150 C. for about /2 hour and cooled to room temperature. The liquid is acidified with concentrated hydrochloric acid and the precipitated crude acid is extracted with 300 ml. of methylene chloride. The methylene chloride solution is washed with about 500 ml. of water and then extracted several times with 2% sodium hydroxide and the basic solution cooled in ice. The solution is acidified with glacial acidic acid, cooled to 5 C., and the acid filtered and dried. The acid is recrystallized from alcohol to yield Z-p-nitrophenyl- 3-(2-thienyl)acrylic acid.

A suspension of 27.2 g. of 2-p-nitrophenyl-3-(2- thienyl)acrylic acid, 10.0 ml. of thionyl chloride and 15 ml. of dry benzene is warmed gently until a solution results. The clear solution is refluxed for about an hour and the excess thionyl chloride and benzene is removed. The solution is further washed with three portions of dry benzene. To the resulting oil is added 9.95 g. of tropine hydrobromide and the mixture is then cooled. To this mixture is added 15 ml. of dry pyridine and the solution is stirred for about /2 hour at room temperature and then at 60 C. to 70 C. for one hour. The mixture solidifies during this process and 30 ml. of dry pyridine is added. Then ml. of water is added and the solution warmed and treated with charcoal. The solution is made basic and the free base is extracted with ether and dried. The pyridine is removed by treatment with several portions of benzene. The benzene is distilled off to yield 3-trop anyl-2-p-nitrophenyl-3 (2-thienyl) acrylate.

A solution of 25.0 g. of 3-tropanyl-p-nitrophenyl-3- (2-thienyl)acrylate in 250 ml. of methane is hydrogenated over platinum on carbon. The reaction mixture is warmed to dissolve the formed solid and the solution is filtered to yield 2,2-p-azoxydiphenylbis[3-(2-thienyl)acrylic acid, 3-tropanyl ester].

An acetone solution of the free base is reacted with maleic acid to yield the maleate salt.

EPMMPLE 6 To a mixture containing 30.0 g. of m-nitrophenylacetic acid, 14.5 ml. of Z-furfural and 24.4 ml. of triethylamine is added 66.4 ml. of acetic anhydride. The mixture is heated on an oil bath at 100 C. for about one hour, cooled to room temperature and taken up in acetone. The solution is heated with activated carbon, filtered and the acetone evaporated. The mixture is then acidified with concentrated hydrochloric acid, cooled and filtered. The crude acid is recrystallized twice from alcohol to yield 2-m-nitrophenyl-3-(2'furyl)acrylic acid.

A suspension of 14.5 g. of 2-m-nitrophenyl-3-(2-furyl)acrylic acid, 10.0 ml. of thionyl chloride and 15 ml. of dry benzene is warmed gently until a solution results. The clear solution is refluxed for about an hour and the excess thionyl chloride and benzene is removed. The solution is further washed with three portions of dry benzene. To the resulting oil is added 11.5 g. of tropine hydrobromide and the mixture is then chilled. To this mixture is added 25 ml. of dry pyridine and the solution is stirred for about /2 hour at room temperature and then at 60 C. to 70 C. for one hour. The mixture solidifies during this process and 25 ml. of dry pyridine is added. Then 100 ml. of Water is added and the solution warmed and treated with charcoal. The solution is made basic and the free base is extracted with ether and dried. The pyridine is removed by treatment with several portions of benzene. The benzene is distilled off to yield 3- tropanyl-2-m-nitrophenyl 3- (Z-furyl) acrylate.

A solution of 40.0 g. of 2.-m-nitrophenyl-3-(Z-furyl)- acrylate in 500 ml. of methane is hydrogenated over platinum on carbon. The reaction mixture is warmed to dissolve the formed solid and the solution is filtered to yield 2,2-m-azoxydiphenylbis[3-(2-furyl)acrylic acid, 3- tropanyl ester].

An acetone solution of the free base is reacted with ethyl bromide to yield the ethobromide quaternary salt.

7 EXAMPLE 7 To a mixture containing 30.0 g. of m-nitrophenylacetic acid, 18.5 g. of 4-pyridylcarboxaldehyde, 24.4 ml. of triethylamine is added 66.4 ml. of acetic anhydride. The mixture is stirred for approximately one hour at room temperature. The solution is cooled and made acetic with concentrated hydrochloric acid. The crude acid is filtered,

dried and recrystallized from alcohol to yield 2-m-nitr0- phenyl-3-(4-pyridyl)acrylic acid.

A suspension of 15.0 g. of 2-m-nitrophenyl-3-(4- pyridyl)acrylic acid, ml. of thionyl chloride and 40 ml. of dry benzene is warmed gently until a solution results. The clear solution is refluxed for about an hour and the excess thionyl chloride and benzene is removed. The solution is further Washed with three separate portions of dry benzene. To the resulting oil is added 10.0 g. of tropine hydrobromide and the mixture is then chilled. To this mixture is added ml. of dry pyridine and the solution is stirred for about /2 hour at room temperature and then at 60 C. to 70 C. for one hour. The mixture solidifies during this process and ml. of dry pyridine is added. Then 100 ml. of Water is added and the solution warmed and treated with charcoal. The solution is made basic and the free base is extracted with ether and dried. The pyridine is removed by treatment with several portions of benzene. The benzene is distilled off to yield 3-tropanyl-2-m-nitrophenyl-3-(4-pyridy1)acrylate.

A solution of 20.0 g. of 3-tropanyl-Z-m-nitrophenyl- 3-(4-pyridyl)acrylate in 250 ml. of methane is hydrogenated over platinum on carbon. The reaction mixture is warmed to dissolve the formed solid and the solution is filtered to yield 2,2-m-azoxydiphenylbis[3-(4-pyridyl) acrylic acid, 3-tropanyl ester].

Reacting the free base with bismethylene-salicylic acid in ethyl acetate solution furnishes the bismethylene-salicylate salt.

EXAMPLE 8 A suspension of 26.0 g. of Z-m-nitrophenyl-B-phenylacrylic acid, as prepared in Example 1, ml. of dry benzene and 20 ml. of thionyl chloride is warmed gently until a solution results. The clear solution is refluxed for about an hour and the excess thionyl chloride and benzene is removed by asperator. The solution is further Washed with three separate portions of dry benzene. To the resulting oil is added 18.2 g. of thiotropine hydrobromide and the mixture is then chilled. To this mixture is added 40 ml. of dry pyridine and the solution is stirred for about /2 hour at room temperature and then at C. to C. for one hour. The mixture solidifies during this process and 20 m1. of dry pyridine is added. Then 200 ml. of water is added and the solution warmed and treated wtih charcoal. The solution is made basic and the free base is extracted with ether and dried. The pyridine is removed by treatment with several portions of benzene. The benzene is distilled ofi to yield 3-thiotropanyl-2-m-nitrophenyl-3-phenyl acrylate.

A solution of 11.8 g. of 3-thiotropanyl Z-m-nitrophenyl-3-phenyl acrylate in ml. of methanol is bydrogenated over platinum on carbon. The reaction mix- 8 ture is warmed to dissolve the formed solid and the solution is filtered.

Hydrogen chloride is bubbled into the filtrate to yield 2,2-m-azoxydiphenylbis[3-phenylacrylic acid, 3-thiotrotropanyl ester] dihydrochloride.

What is claimed is:

1. A chemical compound of the formula or a pharmaceutically acceptable acid addition salt thereof, in which:

X is oxygen or sulfur;

R is phenyl, furyl, thienyl, pyridly or hydrogen; and

R is hydrogen, chlorobromo or fluoro, hydroxy, lower alkyl or lower alkoxy.

2. A chemical compound in accordance with claim 1 in which X is oxygen.

3. A chemical compound in accordance with claim 2 in which R is phenyl.

4. A chemical compound in accordance with claim 3 in which R is hydrogen and the azoxy linkage is in the meta position.

5. A chemical compound in accordance with claim 2 which is 2,2-p-azoxydiphenylbis[acrylic acid, 3-tropanyl ester].

6. A chemical compound in accordance with claim 2 which is 2,2-m-azoxydiphenylbis[3-(2-furyl)acrylic acid, 3-tropanyl ester].

7. A chemical compound in accordance with claim 2 which is 2,2 p azoxydiphenylbis[3-(2-thienyl) acrylic acid, 3-tropanyl ester].

, 8. A chemical compound in accordance with claim 2 which is 2,2 m azoxydiphenylbis[3-(4-pyridyl) acrylic acid, 3-tropanyl ester].

9. A chemical compound in accordance with claim 1 which is 2,2-m-azoxydiphenylbis[Z-phenylacrylic acid, 3- thiotropanyl ester].

References Cited UNITED STATES PATENTS 1,823,743 9/1931 Kalischer et al. 260-143 2,551,894 5/1951 Muller et al. 260143 3,046,271 7/1962 Sackfull et al. 260-l43 3,290,281 12/1966 Weinstein et al. 260-143 FLOYD D. HIGEL, Primary Examiner U .5. Cl. X.R. 

